Enhanced bimatoprost ophthalmic solution

ABSTRACT

A composition comprising from 0.005% to 0.02% bimatoprost by weight and from 100 ppm to 250 ppm benzalkonium chloride, wherein said composition is an aqueous liquid which is formulated for ophthalmic administration is disclosed herein. A method which is useful in treating glaucoma or ocular hypertension related thereto is also disclosed herein.

CROSS-REFERENCE

This is a Continuation of U.S. patent application Ser. No. 13/254,543filed on Sep. 2, 2011, which claims the benefit of a national stageapplication under 35 U.S.C. §371 of PCT patent applicationPCT/US10/26151, filed on Mar. 4, 2010, which claims the benefit of U.S.Provisional Patent Application 61/157,225, filed on Mar. 4, 2009, and isa continuation-in-part of U.S. patent application Ser. No. 12/351,383,filed Jan. 9, 2009 now U.S. Pat. No. 8,338,479 which is a Continuationof U.S. patent application Ser. No. 11/083,261 filed on Mar. 16, 2005which has now issued as U.S. Pat. No. 7,851,504 on Dec. 14, 2010, eachof which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to pharmaceutical compositions comprisingbimatoprost.

2. Description of Related Art

Bimatoprost, shown below, is a prostamide marketed commercially for thetreatment of glaucoma and ocular hypertension.

Benzalkonium chloride (BAK) is a preservative used in many commercialophthalmic products to prevent microbial contamination in multi-useproducts. The commercial eye drops (Bimatoprost, Allergan, Inc., Irvine,Calif.) contain 0.03% bimatoprost and 0.005% BAK. Although no otherprostamides are currently marketed for the treatment of glaucoma,several prostaglandin analogs are commercially available which use BAKas a preservative. These include latanoprost (Xalatan), travoprost(Travatan), and unoprostone isopropyl (Rescula), which requiresignificantly more BAK, from 150-200 ppm, to meet antimicrobialeffectiveness tests in the United States and Europe.

U.S. Pat. No. 6,596,765 B2 discloses a composition comprising 0.005% or0.0005% latanoprost and 0.2 mg/mL BAK.

U.S. Pat. No. 6,646,001 B2 discloses compositions comprising 0.03%bimatoprost and 0.01% BAK or “0.01%+5% excess” BAK.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 is a plot showing the aqueous humor concentration of the parentacid of bimatoprost after topical administration of severalformulations.

FIG. 2 is a plot showing the membrane permeability of bimatoprost inseveral different formulations.

DETAILED DESCRIPTION OF THE INVENTION

Composition comprising from 0.005% to 0.02% bimatoprost by weight andfrom 100 ppm to 250 ppm benzalkonium chloride are disclosed, whereinsaid composition is an aqueous liquid which is formulated for ophthalmicadministration. Methods which are useful in treating glaucoma or ocularhypertension related thereto are also disclosed herein.

An aqueous liquid which is formulated for ophthalmic administration isformulated such that it can be administered topically to the eye. Thecomfort should be maximized as much as possible, although sometimesformulation considerations (e.g. drug stability) may necessitate lessthan optimal comfort.

In certain compositions, the concentration of bimatoprost is from 0.005%to 0.02% w/v. In other compositions the concentration of bimatoprost isfrom 0.01% to 0.02%. In other compositions, the concentration is 0.0125%or 0.015% bimatoprost.

In certain compositions the concentration of BAK is from 50 ppm to 200ppm. In other compositions the concentration of BAK is from 100 ppm to200 ppm. In other compositions the concentration of BAK is from 150 ppmto 250 ppm.

In ophthalmic compositions, a chelating agent may be used to enhancepreservative effectiveness. Suitable chelating agents are those known inthe art, and, while not intending to be limiting, edetate salts (EDTA)are useful chelating agents.

In certain compositions, concentration of EDTA is at least 0.001%. Inother compositions, the concentration of EDTA is at least 0.01%. Inother compositions, the concentration of EDTA is 0.15% or less. In othercompositions, the concentration of EDTA is 0.1% or less. In othercompositions, the concentration of EDTA is 0.05% or less.

As is known in the art, buffers are commonly used to adjust the pH to adesirable range for ophthalmic use. Generally, a pH of around 6-8 isdesired, and in certain compositions a pH of 7.4 is desired. Manybuffers including salts of inorganic acids such as phosphate, borate,and sulfate are known.

Another commonly used excipient in ophthalmic compositions is aviscosity-enhancing agent, or a thickening agent. Thickening agents areused for a variety of reasons, ranging from improving the form of theformulation for convenient administration to improving the contact withthe eye to improve bioavailability. The viscosity-enhancing agent maycomprise a polymer containing hydrophilic groups such asmonosaccharides, polysaccharides, ethylene oxide groups, hydroxylgroups, carboxylic acids or other charged functional groups. While notintending to limit the scope of the invention, some examples of usefulviscosity-enhancing agents are sodium carboxymethylcellulose,hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, andpolyethylene glycol.

In ophthalmic solutions, tonicity agents often are used to adjust thecomposition of the formulation to the desired isotonic range. Tonicityagents are well known in the art and some examples include glycerin,mannitol, sorbitol, sodium chloride, and other electrolytes.

One composition has a pH of 7.4 and consists essentially of 0.015%bimatoprost, 200 ppm benzalkonium chloride, from 0 to 0.03% EDTA, aphosphate buffer, NaCl, and water.

Another composition has a pH of 7.4 and comprises 0.02% bimatoprost, 200ppm benzalkonium chloride, from 0 to 0.03% EDTA, a phosphate buffer,NaCl, and water.

Another composition has a pH of 7.4 and consists of 0.01% bimatoprost,200 ppm benzalkonium chloride, from 0 to 0.03% EDTA, a phosphate buffer,NaCl, and water.

One embodiment comprises 0.01% Bimatoprost, 0.02% Benzalkonium Chloride,0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% Citric Acid,Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is 7.3.

Another embodiment comprises 0.0125% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment comprises 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, 0.03%, EDTA, and water,wherein the pH is 7.3.

Another embodiment comprises 0.02% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment comprises 0.005% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment consists essentially of 0.015% Bimatoprost,0.01%-0.02% Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic,Heptahydrate, 0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride,and water, wherein the pH is 7.3.

Another embodiment consists of 0.015% Bimatoprost, 0.01%-0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, 0.03%, EDTA, andwater, wherein the pH is 7.3.

Another embodiment consists essentially of 0.02% Bimatoprost, 0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, and water,wherein the pH is 7.3.

Another embodiment consists of 0.0125% Bimatoprost, 0.01%-0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, and water,wherein the pH is 7.3.

Another embodiment consists of 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment consists of 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, 0.03%, EDTA, and water,wherein the pH is 7.3.

Another embodiment consists of 0.02% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, EDTA and water, wherein the pHis 7.3.

One embodiment of the present invention is shown below:

Concentration Concentration Reference of Component (% w/v) (mg/mL)Quality Standard Function Bimatoprost 0.01 0.1 In-house standard DrugSubstance Benzalkonium Chloride^(a) 0.02 0.2 NF/Ph Eur PreservativeDibasic Sodium Phosphate 0.268 2.68 USP Buffering Agent HeptahydrateCitric Acid Monohydrate 0.014 0.14 USP/Ph Eur Buffering Agent SodiumChloride 0.81 8.1 USP/Ph Eur Tonicity Agent Hydrochloric Acid^(b) AdjustpH to 7.3 NF/Ph Eur pH Adjuster Sodium Hydroxide^(b) NF/Ph Eur pHAdjuster Purified Water q.s. ad 100 q.s. ad 1 mL USP/Ph Eur Vehicle

Example 1

Formulations containing 0.268% sodium phosphate dibasic heptahydrate,0.014% citric acid, 0.83% sodium chloride, with the pH adjusted to 7.3in qs water, and the amounts of bimatoprost, BAK, and EDTA listed inTable 1 below were prepared by conventional methods well known in theart.

TABLE 1 Formulations 1. 0.03% Bimatoprost (50 ppm BAK) Control 2. 0.03%Bimatoprost - 200 ppm BAK 3. 0.03% Bimatoprost - 0.015% TPGS (nopreservative) 4. 0.03% Bimatoprost - 0.2% TPGS (no preservative) 5.0.03% Bimatoprost - 0.4% TPGS (no preservative) 6. 0.03% Bimatoprost -1.0% TPGS (no preservative)

Example 2

Studies were carried out to determine the effect of benzalkoniumchloride (BAK) and d-alpha tocopheryl polyethylene glycol 1000 succinate(TPGS) on ocular absorption of bimatoprost in vivo. For the in vivostudy, eighteen female rabbits were given a single 28 μL eyedropbilaterally and aqueous humor samples were collected (n=3 animals with 6eyes per formulation) at 60 min postdose. Two rabbits (4 eyes) remaineduntreated to serve as pre-dose bioanalytical controls. Bimatoprost andits parent carboxylic acid extracted from aqueous humor and in vitrosamples were analyzed by a liquid chromatography tandem massspectrometry (LC-MS/MS) method with a quantitation range of 0.25-60ng/mL.

Due to extensive metabolism of bimatoprost in rabbit eyes, its parentacid was used as a surrogate for determining ocular absorption ofbimatoprost. Concentration of the acid in rabbit aqueous humor followingsingle dose of 6 different bimatoprost formulations are summarized inFIG. 1 and Table 2 below.

TABLE 2 Aqueous Humor^(a) Formulations (ng/mL) 1. 0.03% Bimatoprost (50ppm BAK) Control 51.0 ± 9.4 2. 0.03% Bimatoprost - 200 ppm BAK 87.2 ±19.0* 3. 0.03% Bimatoprost - 0.015% TPGS (no 26.1 ± 3.3* preservative)4. 0.03% Bimatoprost - 0.2% TPGS (no 22.9 ± 3.2* preservative) 5. 0.03%Bimatoprost - 0.4% TPGS (no 19.3 ± 5.6* preservative) 6. 0.03%Bimatoprost - 1.0% TPGS (no 15.4 ± 3.3* preservative) ^(a)Mean ± SD. Performulation, N = 3 rabbits (6 eyes). *Statistically different (p < 0.05)compared to 0.03% Bimatoprost

Test formulations containing 0.015%, 0.2%, 0.4% and 1.0% TPGS resultedin a lower aqueous humor carboxylic acid concentration compared toBimatoprost by 52%, 59%, 62% and 72%, respectively. In contrast, 0.03%Bimatoprost containing 200 ppm BAK resulted in 57% higher aqueous humorAGN 191522 concentration compared to Bimatoprost (50 ppm BAK).

While not intending to limit the scope of the invention in any way, orbe bound by theory, compared to the Bimatoprost control, formulationscontaining TPGS resulted in decrease bimatoprost permeability. Incontrast, formulations with higher BAK resulted in higher permeability.

Example 3

Formulations containing 0.268% sodium phosphate dibasic heptahydrate,0.014% citric acid, 0.83% sodium chloride, with the pH adjusted to 7.3in qs water, and the amounts of bimatoprost, BAK, and EDTA listed inTable 3 below were prepared by conventional methods well known in theart.

TABLE 3 Formulations A. 0.03% Bimatoprost (50 ppm BAK) - Control B.0.015% Bimatoprost (50 ppm BAK) C. 0.015% Bimatoprost (50 ppm BAK) 0.03%EDTA D. 0.015% Bimatoprost (200 ppm BAK) E. 0.015% Bimatoprost (200 ppmBAK) 0.03% EDTA F. 0.015% Bimatoprost (50 ppm BAK) 0.015% EDTA G. 0.015%Bimatoprost (200 ppm BAK) 0.015% EDTA H. 0.015% Bimatoprost (125 ppmBAK) I. 0.015% Bimatoprost (125 ppm BAK) 0.03% EDTA J. 0.015%Bimatoprost (125 ppm BAK) 0.015% EDTA K. 0.015% Bimatoprost (150 ppmBAK) L. 0.015% Bimatoprost (150 ppm BAK) 0.1% EDTA M. 0.015% BimatoprostN. 0.03% Bimatoprost

Example 4

The effect of benzalkonium chloride (BAK) and ethylenediaminetetraacetic acid (EDTA) on bimatoprost permeability acrossprimary culture of rabbit corneal epithelial cell layers (RCECL) wasstudied. Corneal epithelial cells were harvested from New Zealand Whiterabbits and cultured on Transwell™ filters until confluency (Day 5). Forthe transport experiment, cells were first equilibrated in transportbuffer for 1 hour at 37° C. Dosing solution containing 0.015% or 0.03%bimatoprost with varying concentrations of BAK and EDTA was then appliedto the apical compartment of the Transwell™ (2 cultures; n=3-4 perculture) and the cells were incubated at 37° C. At 30, 60, 90 and 120minutes postdose, 200 μL samples were taken from the basolateral chamberfor apical to basolateral (AB) transport. The samples were analyzed by aliquid chromatography tandem mass spectrometry (LC-MS/MS) method withquantitation range of 1-600 ng/mL.

The results are presented in FIG. 2.

Example 5

A drop of formulation J (see Table 3) is administered once dailytopically to the eye of a person suffering from glaucoma. After a fewhours, intraocular pressure drops more and less hyperemia is observedthan would be observed for formulation A. Lowered intraocular pressurepersists for as long as the treatment continues.

Example 6

Human patients were instructed to instill 1 drop of the study medication(Bimatoprost 0.01% ophthalmic solution, Bimatoprost 0.0125% ophthalmicsolution or Bimatoprost 0.03% ophthalmic solution (LUMIGAN®) in each eyeonce-daily in the evening. Bimatoprost 0.01% ophthalmic solutioncontained bimatoprost 0.01%, benzalkonium chloride (BAK) 200 ppm, sodiumphosphate dibasic heptahydrate, citric acid, sodium chloride, sodiumhydroxide, hydrochloric acid, and purified water. Bimatoprost 0.0125%ophthalmic solution contained bimatoprost 0.0125%, BAK 200 ppm, sodiumphosphate dibasic heptahydrate, citric acid, sodium chloride, sodiumhydroxide, hydrochloric acid, and purified water. Bimatoprost 0.03%ophthalmic solution (LUMIGAN® (bimatoprost ophthalmic solution) 0.03%contained bimatoprost 0.03%, BAK 50 ppm, sodium phosphate dibasicheptahydrate, citric acid, sodium chloride, sodium hydroxide,hydrochloric acid, and purified water.

Prior to initiation of study treatment, each patient who qualified forentry was assigned a study patient number that was used on all patientdocumentation. Within the series of patient numbers provided to thesite, numbers were assigned in ascending order without omissions.Patients were assigned a treatment group based on a centralrandomisation schedule stratified by baseline (Day 0, Hour 0) IOP andprestudy CCT. Patients were placed into 1 of 6 strata as follows:

TABLE 4 Stratum 1 Stratum 2 Stratum 3 Stratum 4 Stratum 5 Stratum 6 IOPHigh IOP High IOP High IOP Low IOP Low IOP Low (>25 mm Hg) (>25 mm Hg)(>25 mm Hg) (≦25 mm Hg) (≦25 mm Hg) (≦25 mm Hg) CCT Thin CCT Average CCTThick CCT Thin CCT Average CCT Thick (<555 μm) (555-600 μm) (>600 μm)(<555 μm) (555-600 μm) (>600 μm)

Within each stratum, a patient was assigned through the automatedInteractive Voice Response System/Interactive Web Response System(IVRS/IWRS) to either Bim 0.01%, Bim 0.0125%, or Bim 0.03% (LUMIGAN®)once-daily in an even allocation (1:1:1) according to the schedule ofrandomization numbers prepared by Allergan. The automated IVRS/IWRS wasused to manage the randomization and treatment assignment, and sitesdispensed medication according to this system.

At baseline, no statistically significant differences in mean IOP wereobserved between each of the investigational treatments and LUMIGAN®. AtHours 0, 4 and 8, respectively, mean IOP (mm Hg) was [Bim 0.01%: 25.1,23.0, 22.3; Bim 0.0125%: 25.1, 23.0, 22.4; LUMIGAN®: 25.0, 23.2, 22.3].Mean IOP at follow-up ranged from 16.4 to 17.9 mm Hg for Bim 0.01%, 16.6to 18.3 mm Hg for Bim 0.0125%, and 16.1 to 17.8 mm Hg for LUMIGAN®. Bim0.01% was equivalent to LUMIGAN® for mean IOP. For the comparison of Bim0.01% with LUMIGAN®, at 17/17 timepoints, the CIs (95% or 97.5%according to the Hochberg procedure) of the between-treatment differencewere within ±1.50 mm Hg and at 9/17 timepoints were within ±1.00 mm Hg.For the comparison of Bim 0.0125% with LUMIGAN®, at 16/17 timepoints,the CIs (95% or 97.5% according to the Hochberg procedure) of thebetween-treatment difference were within ±1.50 mm Hg, at 2/17 timepointswere within ±1.00 mm Hg, and at 9/17 timepoints were within ±1.16 mm Hg.

Mean Change from Baseline IOP (Non-Inferiority/Superiority at 1.50 mm HgMargin

At baseline, no statistically significant differences in mean IOP wereobserved between each of the investigational treatments and LUMIGAN®. AtHours 0, 4 and 8, respectively, mean IOP was [Bim 0.01%: 25.1, 23.0 and22.3 mm Hg; Bim 0.0125%: 25.1, 23.0, 22.4 mm Hg; LUMIGAN®: 25.0, 23.2,22.3 mm Hg].

All treatments studied showed statistically and clinically significantmean decreases from baseline IOP at all follow-up timepoints (p<0.001).Mean changes from baseline IOP ranged from −5.2 to −7.8 mm Hg for Bim0.01%, −5.2 to −7.5 mm Hg for Bim 0.0125%, and −5.6 to −8.0 mm Hg forLUMIGAN®.

For the comparison of both Bim 0.01% and Bim 0.0125% with LUMIGAN®, at15/17 timepoints, the upper limit of the 95% CI of the between-treatmentdifference was within the 1.50 mm Hg margin.

For 2 timepoints (Week 2/Hour 4, Month 6/Hour 4) the upper limitwas >1.50 mm Hg favouring LUMIGAN® over Bim 0.01% (1.70 mm Hg; 1.53 mmHg, respectively) and Bim 0.0125% (1.67 mm Hg; 1.75 mm Hg,respectively).

Bim 0.01% has an acceptable long-term safety profile with no areas ofparticular concern when administered once-daily for up to 12 months.

Bim 0.01% demonstrated an improved safety profile with a statisticallysignificantly lower incidence of overall adverse events (p=0.010),ocular adverse events (p=0.005), overall treatment-related adverseevents (p=0.016), and ocular treatment-related adverse events (p=0.016)when compared with LUMIGAN®.

LUMIGAN® (0.03% bimatoprost in 50 ppm BAK) has been shown to be both aneffective and safe topical IOP-lowering medication. This 12-month studywas designed to confirm that IOP-lowering efficacy can be maintained andthe safety profile improved by lowering the concentration of the activeingredient and changing the formulation. This was achieved by increasingthe concentration of the preservative BAK from 50 ppm to 200 ppm toensure comparable ocular exposure to that achieved by LUMIGAN®. Twoformulations of bimatoprost (Bim 0.01% and Bim 0.0125%, 200 ppm BAK)were selected for evaluation in this study. A previous paired-eye studyof 4 formulations and LUMIGAN® demonstrated that Bim 0.01% (200 ppm BAK)had superior safety and similar efficacy to LUMIGAN® (192024-030). Inthe same study, Bim 0.015% (200 ppm BAK) also showed comparable efficacyto LUMIGAN® but had a similar incidence of ocular adverse events. Forthe purposes of the present phase 3 study, in addition to Bim 0.01%, aconcentration of bimatoprost between 0.01% and 0.015% was chosen forinvestigation—bimatoprost 0.0125%.

Two primary endpoints were evaluated in this 12 month study. For USregulatory purposes, the primary efficacy endpoint was mean IOP at alltimepoints up to and including the month 3 visit assessed using anequivalence analysis. For EU regulatory purposes, the primary endpointwas mean change from baseline IOP analysed using a strategy ofnon-inferiority and superiority.

All treatments in this study were effective in lowering IOP at allfollow-up timepoints (p<0.001). Mean IOP ranged from 16.4 to 17.9 mm Hgfor Bim 0.01%, 16.6 to 18.3 mm Hg for Bim 0.0125%, and 16.1 to 17.8 mmHg for LUMIGAN® over all post-baseline timepoints. The primary analysisfor US regulatory purposes at 3 months showed that the new formulation,Bim 0.01%, was equivalent in efficacy to LUMIGAN®. The 12 month resultsdemonstrate that Bim 0.01% continues to meet the definition ofequivalence. The 95% and 97.5% confidence intervals (CIs) of thebetween-treatment difference in mean IOP were within ±1.50 mm Hg at all(17/17) post-baseline timepoints and within ±1.00 mm Hg at 9/17post-baseline timepoints. For the comparison of Bim 0.0125% withLUMIGAN®, at 16/17 timepoints, the 95% and 97.5% CIs of thebetween-treatment difference were within ±1.50 mm Hg, at 2/17 timepointswere within ±1.00 mm Hg, and at 9/17 timepoints were within ±1.16 mm Hg.

Mean change from baseline IOP was analysed for EU regulatory purposes.From comparable baseline IOP, mean IOP changes from baseline ranged from−5.2 to −7.8 mm Hg for Bim 0.01%, −5.2 to −7.5 mm Hg for Bim 0.0125%,and −5.6 to −8.0 mm Hg for LUMIGAN®. For the comparison of both Bim0.01% and Bim 0.0125% with LUMIGAN®, at 15/17 timepoints, the upperlimit of the 95% CI of the between-treatment difference was within the1.50 mm Hg margin. For 2 timepoints (Week 2/Hour 4, Month 6/Hour 4) theupper limit was >1.50 mm Hg favouring LUMIGAN® over Bim 0.01% (1.70 mmHg, 1.53 mm Hg, respectively) and Bim 0.0125% (1.67 mm Hg, 1.75 mm Hg,respectively). The PP analyses gave similar results to the ITT analyses.

Secondary non-inferiority analyses showed Bim 0.01% to be non-inferiorto LUMIGAN® for mean IOP (in both the ITT and PP populations), meandiurnal IOP and change from baseline mean diurnal IOP. Bim 0.0125% didnot meet the definition of non-inferiority for mean IOP. In addition,the single secondary analysis for the US regulatory review of meandiurnal IOP, showed Bim 0.01% to be equivalent to LUMIGAN®. Bim 0.0125%did not meet the definition of equivalence for this analysis.

A sensitivity analysis was performed on the PP population for USregulatory purposes. For the comparison of Bim 0.01% with LUMIGAN®, at17/17 timepoints, the 95% CIs of the between-treatment difference werewithin ±1.50 mm Hg, at 6/17 timepoints were within ±1.00 mm Hg, and at9/17 timepoints were within ±1.11 mm Hg. For the comparison of Bim0.0125% with LUMIGAN®, at 17/17 timepoints, the 95% CIs of thebetween-treatment difference were within ±1.50 mm Hg, at 4/17 timepointswere within ±1.00 mm Hg and at 9/17 timepoints were within ±1.19 mm Hg.

The safety results showed an overall improved safety profile for Bim0.01% and Bim 0.0125% compared with LUMIGAN®. An improved macroscopichyperaemia safety profile was observed in the Bim 0.01% and Bim 0.0125%groups compared with the LUMIGAN® group as demonstrated by incidence ofpatients experiencing worsening in severity, at least one clinicallysignificant change from baseline severity grade, peak severity changesfrom baseline and also in mean peak severity. Bim 0.01% consistentlyshowed a superior profile to LUMIGAN® in the severity of macroscopichyperaemia over the 12 month follow-up; the improvement over LUMIGAN®ranged from 20-30% in the mean peak change from baseline of severity(p=0.01).

Biomicroscopic examinations supported these observations. An increasedseverity of conjunctival hyperaemia was more commonly noted withLUMIGAN® (49.2%) than with Bim 0.01% (41.1%) or Bim 0.0125% (35.1%), andthe LUMIGAN® group had consistently more patients with moderate/severehyperaemia over the 12-month study period. Overall, Bim 0.01% showed animproved ocular surface tolerability compared with LUMIGAN®, asdemonstrated by the low incidence of corneal abnormalities on the ocularsurface. Punctate keratitis occurred in only 5 patients (2.7%) receivingBim 0.01% compared with 11 patients (5.9%) receiving LUMIGAN®. These arereassuring findings given the 4-fold increase of BAK in the newformulation.

Overall adverse events, ocular adverse events, overall treatment-relatedadverse events, and ocular treatment-related adverse events werereported by a statistically significantly smaller percentage of patientsin the Bim 0.01% and Bim 0.0125% groups compared with the LUMIGAN®group. No significant differences were seen between the testformulations. The majority of ocular adverse events andtreatment-related adverse events were mild in severity. Conjunctivalhyperaemia was the most frequently reported adverse event and was seenin a significantly smaller percentage of patients in the Bim 0.0125%group (26.6%) compared with the LUMIGAN® group (39.0%; p=0.010). Theincidence of conjunctival hyperaemia in the Bim 0.01% group was 31.4%.There were no notable non-ocular adverse events and incidences wereslightly higher in the Bim 0.01% (43.2%) and LUMIGAN® (41.2%) groupscompared with the Bim 0.0125% (36.7%) group.

Patient's and physician's perceptions of all treatments were positive.The vast majority would have been very/extremely willing to use orprescribe the study treatment and most patients did not experience anychange in eye appearance. This is an important finding as satisfactionwith glaucoma medication is vital for compliance and continuation oftreatment.

CONCLUSIONS

The 12-month results demonstrate equivalence of efficacy between the newformulation of bimatoprost (Bim 0.01%, BAK 200 ppm) and LUMIGAN® (Bim0.03%, BAK 50 ppm) at all timepoints for mean IOP, and non-inferiorityto LUMIGAN® at 15/17 timepoints for mean change from baseline IOP.Compared with LUMIGAN®, Bim 0.01% had significantly fewer adverse events(all causality and treatment-related). Furthermore, patients randomisedto Bim 0.01% experienced less severe macroscopic hyperaemia,significantly fewer ocular adverse events and significantly fewerdiscontinuations due to ocular adverse events.

What is claimed is:
 1. A method of lowering intraocular pressure in aperson with glaucoma or ocular hypertension, the method comprisingadministering once daily to an eye of the person a first compositioncomprising about 0.01% w/v bimatoprost and about 0.02% w/v benzalkoniumchloride, wherein the method lowers intraocular pressure and results inless ocular adverse events as compared to the once daily administrationof a second composition comprising 0.03% w/v bimatoprost and 0.005% w/vbenzalkonium chloride.
 2. The method of claim 1 wherein the firstcomposition has a pH of about 7.3.
 3. The method of claim 1 wherein thefirst composition comprises 0.01% w/v bimatoprost and 0.02% w/vbenzalkonium chloride.
 4. The method of claim 1 wherein the firstcomposition has at least one buffering agent selected from the groupconsisting of dibasic sodium phosphate heptahydrate, citric acidmonohydrate and EDTA.
 5. The method of claim 1 wherein the method iseffective in treating glaucoma.
 6. The method of claim 1 wherein themethod is effective in treating ocular hypertension.
 7. A method oflowering intraocular pressure in a person with glaucoma or ocularhypertension, the method comprising administering once daily to an eyeof the person a first composition comprising about 0.01% w/v bimatoprostand about 0.02% w/v benzalkonium chloride, wherein the method isequivalent in lowering intraocular pressure as compared to the oncedaily administration of a second composition comprising 0.03% w/vbimatoprost and 0.005% w/v benzalkonium chloride.
 8. The method of claim7 wherein the once daily administration of the first composition resultsin less ocular-related adverse events as compared to the once dailyadministration of the second composition.
 9. The method of claim 7wherein the first composition has a pH of 7.3.
 10. The method of claim 7wherein the first composition comprises 0.01% w/v bimatoprost and 0.02%w/v benzalkonium chloride.
 11. The method of claim 7 wherein the firstcomposition results in less macroscopic hyperemia, conjunctivalhyperemia, punctuate keratitis and corneal abnormalities than the secondcomposition.
 12. The method of claim 7 wherein the first composition hasgreater ocular surface tolerability than the second composition.
 13. Themethod of claim 7 wherein the first composition is effective in treatingglaucoma.
 14. The method of claim 7 wherein the first composition iseffective in treating ocular hypertension.
 15. A method for reducing theamount of bimatoprost administered to a person in a once daily treatmentfor glaucoma or ocular hypertension, the method comprising administeringa first composition comprising 0.01% w/v bimatoprost and 0.02% w/vbenzalkonium chloride, wherein the first composition remains useful intreating glaucoma or ocular hypertension despite a lower concentrationof bimatoprost as compared to the once daily administration of a secondcomposition comprising 0.03% w/v bimatoprost and 0.005% w/v benzalkoniumchloride.
 16. The method of claim 15 wherein the once dailyadministration of the first composition results in less hyperemia ascompared to the once daily administration of the second composition. 17.The method of claim 15 wherein the first composition has a pH of 7.3.18. The method of claim 15 wherein the first composition has improvedocular surface tolerability in patients as compared to the secondcomposition.
 19. The method of claim 15 wherein the first composition isa solution.
 20. The method of claim 15 wherein the first composition iseffective in treating elevated intraocular pressure.
 21. The method ofclaim 15 wherein the first composition is effective at treatingglaucoma.
 22. The method of claim 15 wherein the first composition iseffective in treating ocular hypertension.
 23. A method of treatingglaucoma or ocular hypertension comprising administering a firstcomposition administered once daily in a person with glaucoma or ocularhypertension, the first composition comprising 0.01% w/v bimatoprost and0.02% w/v benzalkonium chloride, wherein the first composition lowersintraocular pressure and results in less adverse events, less ocularadverse events and less ocular treatment-related adverse events ascompared to the once daily administration of a second compositioncomprising 0.03% w/v bimatoprost and 0.005% w/v benzalkonium chloride.24. The method of claim 23 wherein use of the first composition resultsin less hyperemia than use of the second composition in patients. 25.The method of claim 23 wherein the first composition is effective attreating glaucoma.
 26. The method of claim 23 wherein the firstcomposition is effective in treating ocular hypertension.
 27. The methodof claim 23 wherein the first composition was equivalent in efficacy inlowering intraocular pressure to the second composition over a threemonth period.
 28. The method of claim 23 wherein use of the firstcomposition results in less macroscopic hyperemia, conjunctivalhyperemia, punctuate keratitis and corneal abnormalities in patientsthan the second composition.